Hyaluronan and its degradation products have opposing effects on experimental autoimmune encephalomyelitis pathogenesis that are dependent and independent of CD44

Multiple sclerosis (MS) involves immune-mediated demyelination and axonal damage, driven by CD4+ T-cell infiltration across the blood-brain barrier (BBB). This work examines the role of hyaluronan (HA) and its receptor CD44 in T-cell capture and rolling on CNS endothelial cells, a key step in extravasation. High-molecular-weight HA tethered by CD44 promoted lymphocyte rolling, while enzymatic HA removal delayed disease onset in EAE models. Surprisingly, HA oligosaccharides (HA12) also reduced disease severity and impaired lymphocyte rolling independently of CD44 or TLR4. These findings identify HA size-specific effects as potential therapeutic targets for limiting immune cell entry in CNS inflammation.